title: Calcium regulation by temperature-sensitive transient receptor potential channels in human uveal melanoma cells.
abstract: Uveal melanoma (UM) is both the most common and fatal intraocular cancer among adults worldwide. As with all types of neoplasia, changes in Ca(2+) channel regulation can contribute to the onset and progression of this pathological condition. Transient receptor potential channels (TRPs) and cannabinoid receptor type 1 (CB1) are two different types of Ca(2+) permeation pathways that can be dysregulated during neoplasia. We determined in malignant human UM and healthy uvea and four different UM cell lines whether there is gene and functional expression of TRP subtypes and CB1 since they could serve as drug targets to either prevent or inhibit initiation and progression of UM. RT-PCR, Ca(2+) transients, immunohistochemistry and planar patch-clamp analysis probed for their gene expression and functional activity, respectively. In UM cells, TRPV1 and TRPM8 gene expression was identified. Capsaicin (CAP), menthol or icilin induced Ca(2+) transients as well as changes in ion current behavior characteristic of TRPV1 and TRPM8 expression. Such effects were blocked with either La(3+), capsazepine (CPZ) or BCTC. TRPA1 and CB1 are highly expressed in human uvea, but TRPA1 is not expressed in all UM cell lines. In UM cells, the CB1 agonist, WIN 55,212-2, induced Ca(2+) transients, which were suppressed by La(3+) and CPZ whereas CAP-induced Ca(2+) transients could also be suppressed by CB1 activation. Identification of functional TRPV1, TRPM8, TRPA1 and CB1 expression in these tissues may provide novel drug targets for treatment of this aggressive neoplastic disease.
authors.affiliation: Charité - Universitätsmedizin Berlin, Campus Virchow-Clinic, Department of Ophthalmology, Augustenburger Platz 1, 13353 Berlin, Germany. Electronic address: stefan.mergler@charite.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mergler
authors.forename: Raissa
authors.initials: R
authors.lastname: Derckx
authors.forename: Peter S
authors.initials: PS
authors.lastname: Reinach
authors.forename: Fabian
authors.initials: F
authors.lastname: Garreis
authors.forename: Arina
authors.initials: A
authors.lastname: Böhm
authors.forename: Lisa
authors.initials: L
authors.lastname: Schmelzer
authors.forename: Sergej
authors.initials: S
authors.lastname: Skosyrski
authors.forename: Niraja
authors.initials: N
authors.lastname: Ramesh
authors.forename: Suzette
authors.initials: S
authors.lastname: Abdelmessih
authors.forename: Onur Kerem
authors.initials: OK
authors.lastname: Polat
authors.forename: Noushafarin
authors.initials: N
authors.lastname: Khajavi
authors.forename: Aline Isabel
authors.initials: AI
authors.lastname: Riechardt
mesh_terms: D048588:Benzoxazines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D015640:Ion Channel Gating / Q000187:drug effects; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D013696:Temperature; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D014604:Uveal Neoplasms / Q000235:genetics* / Q000473:pathology*; D000098943:Uveal Melanoma
chemical_list: D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D011744:Pyrimidinones; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D050051:Transient Receptor Potential Channels; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C490483:icilin; D002211:Capsaicin; D002118:Calcium
keywords: BCTC; CAP; CB1; CPZ; Calcium; Cannabinoid receptor; La(3+); N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide; Planar patch-clamp technique; TRPM; TRPV; TRPV1; Transient receptor potential channels; Uveal melanoma; WIN; WIN 55,212-2; cannabinoid receptor 1; capsaicin; capsazepine; lanthanum chloride; transient receptor potential melastatin; transient receptor potential vanilloid